Intestinal secretory mechanisms and diarrhea

Abstract

One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl^- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. Secretory diarrheas are common and include those induced by pathogenic bacteria and viruses, allergens, and disruptions to bile acid homeostasis, or as a side effect of many drugs. Here, we review the cellular and molecular mechanisms by which Cl^- and fluid secretion in the intestine are regulated, how these mechanisms become dysregulated in conditions of secretory diarrhea, currently available and emerging therapeutic approaches, and how new strategies to exploit intestinal secretory mechanisms are successfully being used in the treatment of constipation.

Keywords: chloride secretion; diarrhea; epithelial transport.

Figure 1.

Intestinal epithelial Cl⁻ secretory mechanism. Chloride secretion is the primary driving force for water secretion across the intestinal epithelium. The energy for this process is derived from the activity of Na⁺-K⁺-ATPase pumps in the basolateral membrane. This transporter exudes 3 Na⁺ from the cell in exchange for 2 K⁺ into the cell with each molecule of ATP consumed. K⁺ is recycled across the basolateral membrane through the cAMP and Ca²⁺-regulated K⁺ channels, KCNQ1 and KCNN4, respectively. Through the activity of the Na⁺-K⁺-ATPase pump, intracellular Na⁺ is maintained at low levels creating a gradient for its entry via the Na⁺-K⁺-2Cl⁻ cotransporter, NKCC1. Since Na⁺ and K⁺ entering the cell via this transporter are recycled across the basolateral membrane, a net increase in chloride concentration inside the cell results, with the result that when the apical Cl⁻ channel, cystic fibrosis transmembrane conductance regulator (CFTR), opens (or other Cl⁻ channels, not shown), there is an electrochemical gradient for chloride secretion into the lumen. Cations, most notably Na⁺, follow passively through the paracellular pathway, with the net accumulation of NaCl in the lumen creating an osmotic gradient that drives water secretion.

Figure 2.

Modulation of intestinal secretory mechanisms as a modality to treat diarrhea. Selected agents discussed in the text are illustrated. In allergic diarrhea, histamine released from mast cells (MC) may evoke calcium-dependent Cl⁻ secretion, which can be blocked by the mast cell stabilizer disodium cromoglycate (DSCG) or antagonists of the histamine H₁ receptor. Excessive release of serotonin (5HT) in patients suffering from carcinoid syndrome also evokes calcium-dependent Cl⁻ secretion; production of 5HT can be inhibited by trilotristat ethyl. Release of excess amounts of vasoactive intestinal polypeptide (VIP) in the setting of VIPoma triggers profound cAMP-dependent Cl⁻ secretion; this action (and release of VIP from the tumor) can be antagonized by somatostatin analogs such as octreotide. Small molecule inhibitors of CFTR or TMEM16A can block Cl⁻ secretion directly, whereas the farnesoid X receptor (FXR) agonist, obeticholic acid, reduces CFTR expression levels. Finally, various resins can sequester prosecretory agents such as bile acids (BA), viruses, and toxins in the intestinal lumen, preventing their interaction with the epithelium. For further details, see text.

Figure 3.

Stimulation of intestinal secretory mechanisms as an emerging modality to treat constipation. Lubiprostone elicits activation of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel (and perhaps other channels) via an increase in cAMP. Linaclotide and plecanatide also activate CFTR and thus Cl⁻ secretion, but by binding to apical guanylyl cyclase-C (GC-C) receptors and thus triggering an increase in cGMP. Elobixat is an inhibitor of the ileal apical Na⁺-coupled bile acid transporter, ASBT. In the presence of this agent, bile acids (BA) accumulate luminally and stimulate Cl⁻ secretion, in part via CFTR. For further details, see text.